1. Field of the Invention
This invention relates to methods and apparatuses for predicting probability of disease recurrence following radical prostatectomy using predetermined clinical and pathological factors. The invention includes nomograms that can be used preoperatively and postoperatively to aid in selection of an appropriate course of therapy.
2. Description of Background
Prostate adenocarcinoma is the most common malignancy in males over the age of 50. Clinically localized prostate cancer is most often treated with conservative management (G. W. Chodak et al., N Engl J Med 330:242-248, 1994; P. C. Albertson et al., JAMA 274:626-63, 1995), external beam irradiation (G. E. Hanks et al., J Urol 154:456-9, 1995; M. A. Bagshaw et al., J Urol 152:1781-5, 1994), or radical prostatectomy (M. Ohori et al., J Urol 154:1818-24, 1995; G. S. Gerber et al., JAMA 276:615-9, 1996; C. R. Pound et al., Urol Clin North Am 24:395-406, 1997; J. G. Trapasso et al., J Urol 152:1821-5, 1996), and occasionally with therapeutic interventions such as interstitial radioactive seed implantation or cryotherapy. Making a decision among the different management choices for clinically localized prostate cancer would be greatly facilitated if reliable predictors of the probability that the selected treatment would control the cancer long term were available. Currently, there are no satisfactory randomized prospective trials comparing cancer control among alternative treatments. Although clinical trials are underway, even when these trials are completed, all patients with a clinically localized cancer will not have an equal probability of a successful outcome.
a. Preoperative Assessment
Prior to undergoing radical prostatectomy, it is of great interest to the patient to know whether the procedure is likely to be curative. Because the pathologic stage of cancer correlates with the probability of recurrence after surgery, a number of investigators have made efforts based on cohort studies to predict the final pathologic stage of prostate cancer using various parameters. A number of nomograms and algorithms have been formulated in an effort to identify the pathological stage of an individual's prostatic cancer. For instance, Partin, et al., has developed a nomogram based on pretreatment prostate specific antigen level (PSA), tumor grade, and clinical stage, to aid physicians in making treatment recommendations by predicting the probability of the final pathological stage of clinically localized prostate carcinoma. (A. W. Partin et al., J Urol 115:110-4, 1993). This nomogram was based on data for one patient population. However, although this nomogram does discriminate between organ-confined and non-confined cancer, it has difficulty predicting high probabilities of seminal vesicle invasion and lymph node metastasis, which are the pathologic features with the most profound impact on prognosis. (M. Kattan et al., Cancer 79:528-537, 1997). In addition, this type of nomogram, including the updated version (Partin et al., JAMA 277:1445-1451, 1997), does not provide the physician with a simple means of advising a patient of the likelihood of recurrence if a radical prostatectomy is performed.
Another algorithm developed pursuant to a study by Badalament et al., purports to predict non-organ confined prostate cancer. This study found that nuclear grade, preoperative PSA, total percent tumor involvement, number of positive sextant cores, preoperative Gleason score, and involvement of more than five percent of a base and/or apex biopsy were significant for prediction of disease organ confinement status. (R. Badalament et al., J Urol 156:1375-1380, 1996).
Another predictor by Narayan et al., uses preoperative serum PSA, biopsy Gleason score, and biopsy-based stage to predict final pathological stage, by constructing probability plots. (P. Narayan et al., Urology 46:205-212, 1995). Yet another predictor by Bostwick et al., uses PSA concentrations, optimized microvessel density of needle biopsy samples and Gleason score to predict extra-prostatic extension. (David Bostwick et al., Urology 48:47-57, 1996).
Existing preoperative predictors typically use final pathologic stage as their end point. (A. W. Partin et al., JAMA 277:1445-1451, 1997). This point is problematic in that some patients with apparently organ confined disease will later develop disease recurrence, whereas many patients with non-organ confined disease will remain disease free. (M. W. Kattan et al., Cancer 793:528-537, 1997). Extracapsular tumor extension, positive surgical margins, seminal vesicle involvement and positive pelvic lymph nodes are adverse pathological features. (A. W. Partin et al., Urol Clin North Am 204:713-725, 1993; J. I. Epstein et al., Cancer 71:3582-3593, 1993; A. Stein et al., J Urol 147:942, 1992). Yet not all patients with one or more of these findings are destined to have disease recurrence after radical prostatectomy. Of the 462 men evaluated by Partin et al. with either focal or established extracapsular penetration (A. W. Partin et al., Urol Clin North Am 20(4):713-725, 1993), only 80 (17%) had evidence of disease recurrence with a mean follow-up of 53 months (range 12 to 120 months). Similarly, Ohori and colleagues report a five-year PSA progression rate of 25% for patients with extracapsular extension in the radical prostatectomy specimen. (M. Ohori et al., Cancer 74:104-14, 1994). In a study of the association between positive surgical margins and disease progression, Epstein et al. found that only half of their patients with positive margins developed disease recurrence. (J. I. Epstein et al., Cancer 71:3582-3593, 1993). Thus, using final pathologic stage as an end point limits the utility of a nomogram to accurately predict disease recurrence following radical prostatectomy. In addition, although final pathology has been associated with eventual treatment failure, none of the existing predictors allow the physician to accurately predict preoperatively the likelihood of recurrence of cancer in a patient if a radical prostatectomy is performed. This is typically the information of greatest interest to the patient before electing to undergo surgery.
There are several established prognostic factors relating to the risk of recurrence after surgery or radiotherapy or the risk of metastasis or death from cancer after conservative management, including clinical stage (M. Ohori et al., Cancer 74:104-14, 1994), Gleason grade (P. C. Albertson et al., JAMA 274:626-631, 1995; G. E. Hanks et al., J Urol 154:456-9, 1995; G. S. Gerber et al., JAMA 276:615-9, 1996) and serum prostate specific antigen (PSA) levels. (G. K. Zagars, Cancer 73:1904-12; 1994). Prior to the present invention, these three routinely available prognostic factors had not been successfully combined into a risk profile that could be used to predict, prior to surgery, the probability of recurrence or metastatic progression after surgical management.
b. Post-Operative Assessment
The most common aggressive therapy for the treatment of clinically localized prostate cancer is radical prostatectomy. Unfortunately, approximately one third of men treated with radical prostatectomy later experience progression of their disease. Typically, the first indication that the disease has progressed occurs as a detectable level of serum PSA months or years following surgery. Early identification, prior to detectable PSA, of men likely to ultimately experience progression would be useful in considering adjuvant therapy or, before documented progression, when adjuvant therapy may be most effective. Accurate identification of the probability of recurrence would also be particularly useful in clinical trials to assure comparability of treatment and control groups or to identify appropriate candidates for investigational treatment such as gene therapy.
Traditionally, the judgment of which patients are at high risk for failure following radical prostatectomy has been based largely on final pathologic stage. As noted, final pathologic stage alone (A. W. Partin et al., JAMA 277:1445-1451, 1997) is a problematic variable for judging high-risk disease since some patients with apparently organ-confined cancer will later develop disease recurrence, and many patients with non-organ-confined cancer will remain disease-free (C. R. Pound et al., Urol Clin North Am 24:395-406, 1997). Not all patients with extracapsular extension or seminal vesicle involvement are destined to have disease recurrence after radical prostatectomy (M. Ohori et al., Cancer 74:104-14, 1994; M. Ohori et al., J Urol 154:1818-1824, 1995; C. R. Pound et al., Urol Clin North Am 24:395-406, 1997; J. G. Trapasso et al., J Urol 152:1821-1825, 1994; A. W. Partin et al., Urol Clin North Am 20:713-725, 1993; J. I. Epstein et al., Cancer 71:3582-3593, 1993). Thus, the use of individual pathologic features appears insufficient to estimate probability for recurrence; a method of combining them is needed.
In 1995, Partin and colleagues (A. W. Partin et al., Urology 45:831-838, 1995) published a model for predicting relative risk that was derived using 216 men with clinical stage T2b and T2c prostate cancer treated by a single urologist. The model utilized pretreatment serum PSA with a sigmoidal transformation, radical prostatectomy Gleason score (Gleason sum), and pathologic stage as specimen confined or nonspecimen confined to identify patients with a high relative risk of recurrence following surgery. Their model computed log relative risk and categorized patients into low, intermediate, and high. In a validation cohort of 214 patients treated by one of three different urologists at two institutions, Partin was able to illustrate that the model was apparently able to stratify those patients as well, based on their Kaplan-Meier PSA recurrence-free survival rates although no statistical testing of strata differences was performed. Bauer et al. (J. J. Bauer et al., J Urol 159:929-933, 1998) recently emulated Partin's approach with 378 patients but added race as a predictor variable and widened the cohort to include all clinical stages up to T1a through T2c. Another difference with the Bauer model was the cutoffs used to distinguish the risk groups (relative risks of 4.0 and 5.75 for Partin versus 10 and 30 for Bauer). Bauer's validation cohort of 99 men indicated a difference in survival rates between the low- and high-risk groups but no difference between intermediate risk and either low or high risk. In another recent study, Bauer (J. J. Bauer et al., Cancer 79(5):952-962, 1997) added biomarkers p53, Ki-67, and bcl-2 to the relative risk calculation. Finally, Harrell et al., discloses a nomogram which evaluates estrogen as a treatment for prostate cancer. This nomogram uses numerous variables, such as age, weight index, blood pressure data, history of cardiovascular disease, tumor size, tumor grade and serum prostatic acid phosphatase to predict survival. (F. Harrell et al., Statistics in Medicine 15:361-387, 1996).
However, none of the postoperative models currently available predict probability of recurrence. Moreover, prior to the present invention, there has been no method or means to predict the probability of treatment failure following surgery, defined as a rising PSA level, following radical prostatectomy for clinically localized prostate cancer. Such risk profiles would be very useful in providing meaningful information to a patient making a decision among courses of therapy. Such a tool would provide the patient with his probability of recurrence instead of a relative risk which is more easily comprehended. While the relative risk informs the patient of his risk of recurring relative to another patient with certain characteristics, the actual probability should more greatly facilitate decision making for the patient.
Therefore, a need has arisen for a method and apparatus to accurately predict prior to surgery the likelihood of recurrence in an individual diagnosed with prostate cancer following radical prostatectomy, using routinely available clinical variables. In addition, a need has arisen for a method and apparatus for accurately predicting probability of recurrence post-prostatectomy, using data routinely collected and available immediately postoperatively, to evaluate whether adjuvant therapy may be warranted before PSA begins to rise.